NF-kB in Health and Disease (eBook)

Contents 6
Contributors 8
99 Understanding the Logic of I kappa B:NF- kappa B Regulation in Structural Terms 10
Abstract 10
1…Introduction 11
2…NF- kappa B and I kappa B 13
3…NF- kappa B Structure and Dimer Formation 16
3.1 Regulation of NF- kappa B Dimerization at the Interface 17
3.2 Regulation of NF- kappa B Dimerization at a Distance 17
3.3 Conditional NF- kappa B Dimerization 18
4…I kappa B Structure and Regulation of NF- kappa B 19
4.1 I kappa B alpha Binding to the NF- kappa B p50:RelA Heterodimer 19
4.2 Regulation of I kappa B alpha :NF- kappa B Complex Formation 20
4.3 The I kappa B beta :RelA Homodimer Complex 21
4.4 NF- kappa B Regulation by I kappa B epsilon 22
4.5 The Non-Classical I kappa B Proteins p105 and p100 22
4.6 Post-Induction Repression of NF- kappa B by I kappa B 23
4.7 Kinetics of I kappa B Degradation 24
5…Recognition of DNA by NF- kappa B 24
5.1 NF- kappa B:DNA Complex Structures 25
5.2 NF- kappa B Recognition of kappa B DNA at the 5vprime-end 26
5.3 NF- kappa B Binding to the Inner Bases of kappa B DNA 27
5.4 Stabilization of NF- kappa B:DNA Complexes 27
5.5 Post-Translational Modification and NF- kappa B:DNA Complex Regulation 28
5.6 NF- kappa B Subunit Exchange in the Nucleus 29
Acknowledgments 29
References 30
107 NF- kappa B/Rel Proteins and the Humoral Immune Responses of Drosophila melanogaster 34
Abstract 34
1…Introduction 35
2…Microbial Recognition and Humoral Responses 36
2.1 Anti-microbial Peptides 36
2.2 Peptidoglycan Recognition and Immune Activation 37
2.2.1 Activation of the Toll Pathway 38
2.2.2 Activation of the IMD Pathway 41
3…Intracellular Signaling in the Toll and IMD Pathways 42
3.1 Toll Pathway 42
3.2 IMD Pathway 43
4…NF- kappa B Proteins 45
4.1 Dorsal and DIF 48
4.2 Relish 49
4.3 Transcriptional Regulation of NF- kappa B Targets 50
5…Co-activators of Drosophila Rel Proteins 53
6…Negative Regulators of the Toll and IMD Pathways 54
6.1 Catalytic PGRPs 54
6.2 Negative Regulators of Toll Signaling 55
6.3 Negative Regulators of IMD Signaling 56
7…Beyond AMPs 58
7.1 Anti-viral Immunity 58
7.2 Adaptive Immunity in Drosophila 59
8…Concluding Remarks 59
References 60
106 Specialized Chromatin Patterns in the Control of Inflammatory Gene Expression 70
Abstract 70
1…Specialization and Selectivity in the Inflammatory Gene Expression Programs 71
2…Specialized Chromatin Organizations at Different Groups of Inflammatory Genes 71
3…The Genomic Determinants of Nucleosomal Organization at Inflammatory Genes 72
4…A Role of the Nucleosome Barrier in Stimulus-selective Gene Induction 76
5…Chromatin Remodeling and Kinetics of NF- kappa B Activation: A Complex Interplay 77
6…Conclusions 79
Acknowledgments 79
References 79
98 IKK Regulation and Human Genetics 82
Abstract 82
1…Introduction 83
2…The Kinase Subunits 83
3…The NEMO/IKK gamma Regulatory Subunit: Structure and Function 85
4…Other Post-translational Modifications of NEMO 90
5…IKK-Related Genetic Diseases 91
5.1 Incontinentia Pigmenti (IP) 92
5.1.1 Main Features of IP 92
5.1.2 Genetics of IP 92
5.1.3 Pathophysiology of IP 93
5.2 Anhidrotic Ectodermal Dysplasia with Immunodeficiency 94
5.3 Molecular Basis of NEMO-Related Pathologies 97
6…Are there other Components in the IKK Complex? 98
References 99
101 Control of NF- kappa B Activity by Proteolysis 105
Abstract 105
1…Regulation of NF- kappa B Activity by the Proteasome 106
1.1 The Ubiquitin and Proteasome System 106
1.2 Degradation of ‘‘small’’ I kappa Bs 106
1.3 Processing and Degradation of NF- kappa B1 and NF- kappa B2 Precursors 108
1.4 Degradation of Mediators of the NF- kappa B Signaling Cascades 109
1.5 Degradation of NF- kappa B Proteins 112
2…Regulation of NF- kappa B Activity by Caspases 113
3…Regulation of NF- kappa B Activity by Calpains 115
4…Conclusion 115
References 115
102 NF- kappa B and Innate Immunity 123
Abstract 123
1…Introduction 125
2…Activation of NF- kappa B by Toll-Like Receptors 126
2.1 MyD88 and TRIF-Dependent Signaling 127
2.2 IKK-Related Kinases: TBK1 and IKK-i 128
2.3 Canonical IKK Kinases in IRF Activation 128
2.4 IFN-Regulated Induction of NF- kappa B 129
3…Intracellular Pattern Recognition Receptors 129
3.1 Cytoplasmic RIG-I Like Receptors 129
3.2 Intracellular DNA Recognition 130
3.3 NF- kappa B Activation Downstream of Cytoplasmic Receptors 130
3.4 Nod-Like Receptors 131
4…Viral Modulation of NF- kappa B Activity 131
4.1 Viral Genomes Containing NF- kappa B Elements 131
4.2 Modulation of Apoptotic Pathways 132
4.3 Bi-Phasic Control of NF- kappa B During Viral Infection 133
5…NF- kappa B: Transcriptional Regulation and Gene Targets in the Innate Response 133
5.1 Induction of PAMP-Specific Cytokines and Chemokines 133
5.1.1 NF- kappa B Sequence Diversity and Dimerization 134
5.1.2 Stimulus Specific Gene Expression via NF- kappa B Dynamic Control 134
5.1.3 Temporal Recruitment of NF- kappa B Members 135
5.2 NF- kappa B Regulation of Specific Genes 136
5.2.1 Regulation of the IFN- beta Enhanceosome 136
5.2.2 Regulation of the Interleukin 12 p40 Locus 138
6…Negative Regulation of NF- kappa B 139
6.1 Induction of I kappa B Family Members 139
6.2 Negative Regulators Upstream of the IKK Complex 139
6.3 Induction of Anti-Inflammatory Cytokines 140
6.4 NF- kappa B Induced Tolerance 140
7…Physiological Roles of NF- kappa B in Innate Immunity 141
7.1 RelA (rela) 141
7.2 RelB (relb) 141
7.3 c-Rel (rel) 142
7.4 p50/p105 (NF- kappa B1) 142
7.5 p52/p100 (NF- kappa B2) 144
8…Conclusion 144
References 145
103 NF- kappa B and Mucosal Homeostasis 152
Abstract 152
1…Introduction 153
2…NF- kappa B in Intestinal Homeostasis 154
3…NF- kappa B in Protection Against Acute Intestinal Injury 155
4…NF- kappa B in Mucosa--Microbe Interactions 156
5…Basal Activation of Mucosal NF- kappa B 157
6…Microbial Modulation of NF- kappa B Signaling: Commensals and Pathogens 159
6.1 Commensals 159
6.2 Pathogens 160
7…Summary 161
References 161
97 IKK- and NF- kappa B-Mediated Functions in Carcinogenesis 166
Abstract 166
1…Nuclear Factor kappa B (NF- kappa B) Signaling Pathway 167
2…Different Ways to Activate NF- kappa B in Hematological and Solid Malignancies 167
3…Cell Autonomous and Non-Autonomous Functions of NF- kappa B During Tumorigenesis 168
4…NF- kappa B and Pancreatic Cancer 170
5…NF- kappa B is Involved in Expansion of Tumor Stem Cells During Tumor Initiation 172
6…Distinct Functions of IKK alpha During Tumorigenesis 173
7…Therapeutic Implications 173
References 174
100 Macrophages and NF- kappa B in Cancer 177
Abstract 177
1…Tumor-Associated Macrophages 178
1.1 Angiogenesis 180
1.2 Invasion and Metastasis 181
1.3 Immune-Suppression 181
2…NF- kappa B Activation and TAM 182
3…Pro- or Anti-Inflammatory Roles for NF- kappa B in TAM? 183
4…What Drives NF- kappa B Activation in TAM? 185
5…‘Re-educating’ TAM by Targeting NF- kappa B 186
References 187
104 NF- kappa B in Liver Cancer: The Plot Thickens 191
Abstract 191
1…NF- kappa B and Human HCC 193
2…Mouse Models of HCC 193
3…Mouse Model-Based Evidence that NF- kappa B Plays a Pro-Oncogenic Role in HCC 194
4…Mouse Model-Based Evidence that NF- kappa B Functions as a Tumor Suppressor in HCC 195
Acknowledgments 198
References 198
108 NF- kappa B as a Target for Oncogenic Viruses 203
Abstract 203
1…Introduction 205
2…NF- kappa B Activation by HTLV1 206
2.1 HTLV1 and Adult T Cell Leukemia 206
2.2 Tax as a Primary Oncogenic Mediator of HTLV1 207
2.3 Persistent Activation of NF- kappa B by Tax 208
2.4 Targeting IKK Signaling Components by Tax 209
2.5 Tax-Specific Mechanism of Noncanonical NF- kappa B Activation 211
2.6 Ubiquitination in Tax-Mediated IKK/NF- kappa B Activation 213
2.7 Tax-Independent Activation of NF- kappa B in ATL Cells 215
2.8 NF- kappa B in HTLV1-Stimulated T Cell Transformation 216
3…NF- kappa B Activation by KSHV 217
3.1 Diseases Associated with KSHV Infection 217
3.1.1 Kaposi’s Sarcoma (KS) 217
3.1.2 Primary Effusion Lymphomas (PEL) 218
3.1.3 Multicentric Castleman’s Disease 219
3.1.4 Plasmablastic Lymphomas Associated with MCD 220
3.2 KSHV Latent and Lytic Infection 220
3.3 NF- kappa B in KSHV Infection and Reactivation 221
3.3.1 NF- kappa B During KSHV Binding and Entry 221
3.3.2 NF- kappa B During KSHV Latency 221
3.3.3 NF- kappa B in KSHV Lytic Reactivation 222
3.4 Mechanism of NF- kappa B Activation by vFLIP 224
3.5 Role of NF- kappa B in KSHV-Mediated Oncogenesis 225
4…NF- kappa B Activation by EBV 225
4.1 EBV Infection in Healthy Humans and EBV Life Cycle 225
4.2 Diseases Caused by EBV Infection 227
4.2.1 Burkitt’s Lymphoma (BL) 228
4.2.2 Post-Transplantation Lymphoproliferative Disorder 228
4.2.3 AIDS-Related Non-Hodgkin’s Lymphomas 229
Lymphomas also Occurring in Immunocompetent Patients 229
Lymphomas Occurring Primarily in HIV-Positive Patients 229
4.2.4 T/natural Killer Cell Lymphomas 230
4.2.5 Hodgkin’s Lymphoma (HL) 230
4.2.6 Nasopharyngeal Carcinoma (NPC) 230
4.3 NF- kappa B Activation During EBV Binding and Entry 231
4.4 NF- kappa B During Latent EBV Infection 231
4.5 NF- kappa B in Lytic Reactivation of EBV Reactivation 232
4.6 Mechanism of NF- kappa B Activation by the Latent Viral Proteins LMP1 and LMP2 232
4.7 Role of NF- kappa B in EBV-Mediated Oncogenesis 234
5…Concluding Remarks 234
Acknowledgments 235
References 235
105 Inhibition of NF- kappa B Signaling as a Strategy in Disease Therapy 251
Abstract 251
1…Introduction to NF- kappa B Transcription Factors 252
2…Regulation of NF- kappa B Signaling 253
3…Introduction to Inhibition of NF- kappa B Signaling 254
3.1 Receptor-Based Inhibition of NF- kappa B 256
3.2 Adaptor-Based Inhibition of NF- kappa B Signaling 256
3.3 Inhibition of IKK 257
3.4 Inhibition of I kappa B Degradation 258
3.5 Inhibition of NF- kappa B Nuclear Translocation 259
3.6 Inhibition of NF- kappa B-Dependent DNA Binding and Transactivation 260
4…Inhibition of NF- kappa B as Anticancer Therapy: Multiple Myeloma and Diffuse Large B-cell Lymphoma as Models 261
5…Inhibition of Specific NF- kappa B Subunits as a Therapeutic Strategy: c-Rel as a Target 262
6…Summary and Perspectives 263
Acknowledgments 264
References 264
Index 270